Neurotransmitter serotonin or 5-Hydroxytryptamine (5-HT) is abundantly distributed in the central nervous system, including hippocampus and frontal cortex. 5-HT receptors are a family of G-protein coupled receptors, characterized with 7-transmembrane helices and presently have fourteen known receptor subtypes, some of which exist as multiple splice variants [D. L. Murphy, A. M. Andrews, C. H. Wichems, Q. Li, M. Tohda and B. Greenberg, J. Clin. Psychiatry, 1998, 59 (suppl. 15), 4]. 5-HT influences a number of physiological functions and is implicated in a large number of central nervous system disorders and neurodegenerative diseases [W. E. Childers, Jr. and A. J. Robichaud, Ann. Rep. Med. Chem. 2005, 40, 17].
The 5-HT4 receptors are a member of the superfamily of G-protein coupled receptors with seven transmembrane (7TM) domains coupled to a G-protein which is positively coupled to adenylate cyclase. The 5-HT4 receptors are expressed in a wide variety of tissues, including the human brain and the rodent brain, and human, dog, pig and rodent gastro-intestinal tract, and the pig and human heart. In the human brain, the presence of 5-HT4 receptors has been shown in basal ganglia and in the caudate putamen nuclei, where the density is the highest [Bonacenture, Hall, Gommersen, Cras, langlois, Jurzak, Leysen, Synapse, 2000, 36, 35]. In the mammalian brain, the 5-HT4 receptors contribute to dopamine secretion and regulate learning and long-term memory via the modification of acetylcholine release. In the central nervous system of guinea-pigs and rats, 5-HT4 receptors are expressed in two anatomical and functional structures: the extrapyramidal motor system and the mesolimbic system [Patel, Roberts, Moorman, Reavill, Neuroscience, 1995, 69, 1159; Grossman, Kilpatrik, Bunce, Br. J. Pharmacol. 1993, 109, 618].
In the peripheral tissues, the 5-HT4 receptors have proven to regulate gastro-intestinal tract motility, intestinal electrolyte secretion, adrenal secretion of corticosteroids, bladder contraction and atrium contractility. Significant advances have been made in the 5-HT4 receptor studies during the past decade that culminated in the development of 5-HT4 agonists and partial agonists, e.g. Tegaserod, for the treatment of irritable bowel syndrome [Giger, Mattes, Pfannkuche, Ann. Rep Med. Chem. 2007, 42, 195].
The 5-HT4 receptors are involved in a wide variety of central and peripheral disorders, including neurodegenerative disorders such as Alzheimer's disease, cognition disorders, irritable bowel syndrome, nausea, emesis, vomiting, prokinesia, gastroesophageal reflux disease, nonulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhthymia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, feeding disorders, gastrointestinal disorders, constipation, erectile dysfunction, and respiratory depression.
The role of the 5-HT4 receptor has been implicated in the pathology of Alzheimer's disease and related cognitive function [J. Bockaert, S. Claeyseen, V. Compan and A. Dumuis. Curr. Drug. Targets: CNS & Neurolog. Disorders, 2004, 3, 39; P. C. Moser, O. E. Bergis, S. Jegham, A. Lochead, E. Duconseille, T. Elee, J.-P. Terranova, D. Caille, I. Berque-Bestel, F. Lezoualch, R. Fischmeister, A. Dumuis, J. Bockaert, G. Pascal, P. Soubrie and B. Scatton, J. Pharmacol. Exp. Ther. 2002, 302, 731]. A recent report provides evidence from transgenic animal studies that supports the finding that the 5-HT4 receptor is a novel target for cognitive enhancement and that only a partial agonist is needed for producing the beneficial effect in increasing cognition function. Moreover, the 5-HT4 receptor remains functional even in the presence of excess of A□ □ for Alzheimer's drug discovery [J. P. Spencer, J. T. Brown, J. C. Richardson, A. D. Medhurst, S. S. Sehmi, A. R. Calver, A. D. Randall, Neuroscience, 2004, 129, 49]. Stimulation of the 5-HT4 receptor promotes an increase in the production and release of acetylcholine (ACh) in the brain unlike the cholinesterase inhibitors that prevent degradation of ACh for symptomatic improvement in Alzheimer's disease patients. The activation of 5-HT4 receptor also leads to secretion of the soluble form of amyloid precursor protein (sAPPα), and decrease in Aβ levels via promoting the a-secretase pathway [M. Cachard,-Chastel, F. Lezoualc'h, I. Dewachter, C. Delomenie, S. Croes, H. Devijver, M. Langlois, F. V. Leuven, S. Sicsic, and A. M. Gardier. Brit. J. Pharmacol. 2007, 150, 883]. Evidence in vivo rat studies of the role of activation of 5-HT4 receptor in the production of sAPPαhas recently been reported [S. Cho and Y. Hu, Exper. Neurology, 2007, 203, 274]. The protein, sAPPα is neuroprotective, enhances memory, increases NGF and competes with amyloidogenic (insoluble) APP peptides. Considering the significant evidence reported, it is evident that 5-HT4 receptor agonists may have potential not only in the treatment of Alzheimer's disease but also modification of the disease by slowing and inhibiting its progression [F. Lezoualc'h, Exper. Neurology, 2007, 205, 325].
The novel compounds of formula I have 5-HT4 partial agonist activity and/or full agonist activity, inverse agonist activity and antagonist activity and have applications as safer and effective therapeutic drugs for the treatment of Alzheimer's disease and age-related cognitive and memory dysfunction and cognitive and memory impairment associated with schizophrenia. These compounds may also have applications in the treatment of gastrointestinal disorders including irritable bowel syndrome, Crohn's disease, gastroesophageal reflux disease, emesis, nausea, vomiting, prokinesia, non-ulcer dyspepcia, anxiety, depression, pain, migraine, urinary incontinence, arterial fibrillation, arrhythmia, ischemic stroke, gastric emptying disorders, gastritis, gastrointestinal disorders, feeding disorders, obesity, anorexia, constipation, constipation, respiratory depression, and erectile dysfunction.